Huntington's Disease (HD) is a neurodegenerative disorder that is defined by the accumulation of nanoscale aggregates comprised of the huntingtin (htt) protein. Aggregation is directly caused by an expanded polyglutamine (polyQ) domain in htt, leading to a diverse population of aggregate species, such as oligomers, fibrils, and annular aggregates. Furthermore, the length of this polyQ domain is directly related to onset and severity of disease. The first 17 N-terminal amino acids of htt have been shown to further modulate aggregation. Additionally, these 17 amino acids appear to have lipid binding properties as htt interacts with a variety of membrane-containing structures present in cells, such as organelles, and interactions with these membrane surfaces may further modulate htt aggregation. To investigate the interaction between htt exon1 and lipid bilayers, in situ atomic force microscopy (AFM) was used to directly monitor the aggregation of htt exon1 constructs with varying Q-lengths (35Q, 46Q, 51Q, and myc-53Q) on supported lipid membranes comprised of total brain lipid extract. The exon1 fragments accumulated on the lipid membranes, causing disruption of the membrane, in a polyQ dependent manner. Furthermore, the addition of an N-terminal myc-tag to the htt exon1 fragments impeded the interaction of htt with the bilayer.

Prion diseases are neurodegenerative diseases associated with a conformational change of the normal cellular form of the prion protein (PrP C) to an abnormal aggregated form (PrP Sc). Recent research suggests that oligomeric rather than plague forms of prion protein (PrP) are the main toxic species, but it is not clear how they lead to disease development. However, the interactions of PrP with membranes have been reported to affect the behavior of PrP, and have been implicated in the toxicity of oligomers. To gain insight into the molecular basis of this effect, we use coarse-grained molecular simulations to study the ability of several amyloidogenic PrP and yeast prion protein fragments to interact with zwitterionic and anionic model membranes. Monomeric and oligomeric forms of PrP are studied in water and in the presence of phosphatidylcholine (POPC) and phosphatidylserine (POPS) bilayers. The conformation of PrP and peptidelipid interactions are characterized, and the influence of peptide binding to different lipid bilayers on the aggregation process is analyzed.